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Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear...

The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.

Cardiovascular disturbances are a frequent occurrence in neonatal sepsis. Preterm and term infants are particularly vulnerable due to the unique features of their cardiovascular function and reserve, compared to older children and adults. The clinical manifestations of neonatal sepsis are a product of the variable inflammatory pathways involved (warm vs. cold shock physiology), developmental state of the cardiovascular system, and hormonal responses. Targeted neonatal echocardiography has played an important role in advancing our knowledge, may help delineate specific hemodynamic phenotypes in real-time, and supports an individualized physiology-based management of sepsis-associated cardiovascular dysfunction. IMPACT: Cardiovascular dysfunction is a common sequela of sepsis. This review aims to highlight the pathophysiological mechanisms involved in hemodynamic disturbance in neonatal sepsis, provide insights from targeted neonatal echocardiography-based clinical studies, and suggest its potential incorporation in day-to-day management.

The association between psoriasis, metabolic syndrome, andcardiovascular disease is well established. The shared pathways between psoriasis, metabolic syndrome, and atherosclerosis suggest that treatments targeting the inflammatory pathways of psoriasis may also be beneficial in the treatment of associated cardiometabolic comorbidities. This paper reviews the most recent data regarding the impact of systemic psoriasis treatments on comorbid cardiovascularandmetabolic disease. Data from randomized clinical trials with systemic and biologic agents are presented. Overall, studies demonstrate beneficial effects on several cardiometabolic markers and risk factors in psoriasis patients; however, longer randomized controlled trials to characterize the direct benefit for cardiovascular outcomes are needed.

Introduction Understanding the pathogenesis and risk factors to control the coronavirus disease 2019 (COVID-19) is necessary. Due to the importance of the inflammatory pathways in the pathogenesis of COVID-19 patients, evaluating the effects of anti-inflammatory medications is important. Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is awell-known glucose-lowering agent with anti-inflammatory effects. Areas covered Resources were extracted from the PubMed database, using keywords such as glucagon-like peptide-1, GLP-1 RA, SARS-CoV-2, COVID-19, inflammation, in April2021. In this review, the effects of GLP-1RA in reducing inflammation and modifying risk factors of COVID-19 severe complications are discussed. However, GLP-1 is degraded by DPP-4 with aplasma half-life of about 2–5 minutes, which makes it difficult to measure GLP-1 plasma level in clinical settings. Expert opinion Since no definitive treatment is available for COVID-19 so far, determining promising targets to design and/or repurpose effective medications is necessary.

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established.

Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.

Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

Kgengwe fruits are commonly consumed in sub-Saharan countries. Recent reports indicated low coronary artery disease rates in those regions. To investigate anti-atherogenic properties and potential mechanisms of action of Kgengwe seed powder (KSP), male low-density lipoprotein receptor knockout (LDL-r-KO) mice were fed with an atherogenic diet supplemented with (treated, n = 10) or without (controls, n = 10) 10% (w/w) KSP for 20 weeks. Proximate analysis revealed that KSP contained 38% fibre and 15% lipids. KSP supplementation was not associated with significant changes in body weight gain rate, food intake, and plasma lipid levels. However, the average atherosclerotic lesion size in the aortic roots in the KSP-treated group was 58% smaller than that in the control group (0.26 vs 0.11 mm2, p < 0.05). This strong anti-atherogenic effect was associated with significant increases in the average plasma levels of certain cytokines such as IL-10 (6 vs 13 pg/mL, p < 0.05), GM-CSF (0.1 vs 0.2 pg/mL, p < 0.05), and EPO (7 vs 16 pg/mL, p < 0.05) along with reductions in the average levels of plasma MCP-1 (19 vs 14 pg/mL, p < 0.05) and MIP-2 (28 vs 13 pg/mL, p < 0.05). Except for relatively high levels of saturated fatty acids, KSP possesses balanced nutrient compositions with strong anti-atherogenic properties, which may be mediated through alterations in inflammatory pathways. Additional studies warrant confirmation and mechanism(s) of action of such effects. Novelty: Kgengwe seeds prevent atherogenesis in LDL-r-KO mice. Kgengwe seeds increase circulating levels of IL-10 and EPO. No reduction in plasma total cholesterol levels.

Bacteria-induced acute lung injury (ALI) is associated with a high mortality rate due to the lack of an effective treatment. Patients often rely on supportive care such as low tidal volume ventilation to alleviate the symptoms. Nanomedicine has recently received much attention owing to its premium benefits of delivering drugs in a sustainable and controllable manner while minimizing the potential side effects. It can effectively improve the prognosis of bacteria-induced ALI through targeted delivery of drugs, regulation of multiple inflammatory pathways, and combating antibiotic resistance. Hence, in this review, we first discuss the pathogenesis of ALI and its potential therapeutics. In particular, the state-of-the-art nanomedicines for the treatment of bacteria-induced ALI are highlighted, including their administration routes, in vivo distribution, and clearance. Furthermore, the available bacteria-induced ALI animal models are also summarized. In the end, future perspectives of nanomedicine for ALI treatment are proposed.

There is close association between asthma and cardiovascular functions as both diseases share common inflammatory pathways. The current study was aimed at investigating the risk factors, associated with endothelial and cardiac functions in children with newly-diagnosed mild-persistent asthma.A total of 33 steroid-naive asthmatic children [median(interquartile-range); 9.1 years(7.8-13.5)] and 16 healthy controls [11.5 years(9.9-13.6)] were included. Their demographic, clinical and laboratory findings were recorded. Carotid Artery intima-media thickness (CIMT), stiffness, distensibility and strain were measured as atheroclerosis markers. Conventional and tissue Doppler imaging was performed to evaluate ventricular function.The patients with asthma had higher CIMT and stiffness and lower strain and distensibility compared to controls (Children with mild persistent asthma had subclinical atherosclerosis and ventricular dysfunction even in the early stage of disease. Symptom duration was closely associated with both subclinical atherosclerosis and ventricular dysfunction. Myocardial performance index was abnormal in the asthmatic children when assessed by tissue Doppler Imaging even though they had normal ejection fraction in conventional echocardiography. Future prospective studies with larger sample sizes are needed to confirm these findings and to assess the possible protective effect of ICSs in the prevention of subclinical atherosclerosis.

Background: Basic Fibroblast growth factor (bFGF) increases proliferation of melanocytes in the pigmentation of vitiligous area. Tacrolimus is well established topical immunomodulator with action at multiple immune as well as inflammatory pathways. The combination of treatment modalities acting via different mechanisms have proven beneficial in management of vitiligo Materials and Methods: A phase IV, randomized, open label, non-comparative, prospective, multicenter study conducted among patients with stable vitiligo to evaluate efficacy and safety of topical combination of bFGFrP and tacrolimus in comparison with tacrolimus monotherapy. The efficacy assessment parameters after 12 months of treatment were, improvement in extent of repigmentation (EOR), grade of repigmentation (GOR), patient global assessment (PGA). Results: Out of 120 randomized patients, at the end of the study, after 12 months of treatment, the combination group (bFGFrP + T) showed significant improvement in EOR with 66.7% patients (n=54) achieving greater than 50% of repigmentation as compared to only 39.2% in tacrolimus group (n=51). Significantly higher mean response rate (66.75%) was observed in combination group than tacrolimus monotherapy group (46.47%). Conclusion: After 12 months of treatment, combination of bFGFrP and Tacrolimus leads to significantly better results with rapid repigmentation and response rates in stable vitiligo patients, with a favorable safety profile. Keywords: Vitiligo, BFGF related decapeptide, Tacrolimus, Repigmentation, Extent of repigmentation, Response rates.

The neurohumoral and inflammatory pathways proposed for the development and progression of heart failure (HF) remain up-to-date. We aimed to investigate the effect of emergency department (ED) visits and inflammatory markers on mortality in HF patients. Two-hundred patients with stable chronic HF followed by the cardiology clinic were included in this study. The patients were divided into two groups as patients who had visited the ED due to worsening HF symptoms within the last 6 months (ED visit Group) and who had not (No ED visit Group). The demographical properties, clinical characteristics, and laboratory values including inflammatory markers of the patients were recorded. During the follow-up period, 38 patients (19%) died. In HF patients with previous ED visits, the mortality risk was 2.091 times higher (relative risk, RR). It was identified that the HF patients who died during the follow-up had higher initial NLR (p = 0.004), IG% (p = 0.029), hs-CRP (p = 0.001), and NT-proBNP (p = 0.004) values. It was observed that the area under the curve (AUC) values, NLR (AUC: 0.705, p 0.001), IG% (AUC: 0.652, p = 0.003), and hs-CRP (AUC: 0.732, p 0.001) were very strong predictors of the 1-year mortality. According to the cut-off points, the mortality risk (RR) was 3.39 times higher in patients with NLR 3.7 (95% CI 1.783-6.444), 2.39 times higher when IG% 0.4 (95% CI 1.16-4.957), and 4,2 times higher when hs-CRP 9.9 mg/dl (95% CI 2.16-8.16) (p 0.05). The patients with chronic stable HF who visited the ED within the last six months and having increased NLR, IG%, and CRP levels among inflammatory markers were associated with a higher mortality risk at 1 year.

The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals. Using an integrative bioinformatics approach, we systematically scanned 2001 environmental chemicals and identified 50 chemicals that consistently dysregulate two transcriptional signatures of critical period plasticity. These chemicals included pesticides (e.g., pyridaben), antimicrobials (e.g., bacitracin), metals (e.g., mercury), anesthetics (e.g., halothane), and other chemicals and mixtures (e.g., vehicle emissions). Application of a chemogenomic enrichment analysis and hierarchical clustering across these diverse chemicals identified two clusters of chemicals with one that mimicked an immune response to pathogen, implicating inflammatory pathways and microglia as a common chemically induced neuropathological process. Thus, we established an integrative bioinformatics approach to systematically scan thousands of environmental chemicals for their ability to dysregulate molecular signatures relevant to critical periods of development.

Chronic rhinosinusitis (CRS) is a heterogeneous disease process with a complex underlying cause. Improved understanding of CRS pathophysiology has facilitated new approaches to management of the patient with CRS that rely on targeting patient-specific characteristics and individual inflammatory pathways. A more personalized approach to care will ultimately incorporate a combination of phenotypic and endotypic classification systems to guide treatment. This review summarizes current evidence with respect to CRS phenotypes and endotypes, as well as the identification of potential biomarkers with potential to guide current and future treatment algorithms.

Degenerative disc disease (DDD) is a common condition causing low-back pain, disability and, eventually, neurological symptoms. This investigation aimed to investigate intervertebral disc DDD-related changes, evaluating histomorphology and cytokines secretion, and their clinical-radiological correlations.This is a monocentric prospective observational study. A cohort of patients who underwent microdiscectomy for DDD, from June 2018 to January 2019, were enrolled. Discs samples were examined for histomorphology, chondrons count, immunohistochemistry for Hif-1α, Nf200 and Egr-1. Demographical and clinical data were also collected.Twenty patients were finally included. MRI evaluation showed a Modic I alteration in nine patients and a Modic II in 11. The disability grade was low-moderate (ODI score was ≤ 40%) in eight patients and high (ODI score 40%) in 12. The Modic I was associated with a low-moderate disability in two (22%) patients and to a high disability in seven (88%) (p 0.01). In Modic I group and in ODI 40% groups, there were a significative higher mean disability grade 48.4 (± 8.3)%, number of chondrons per section, cells per chondron, Nf200+ nerve fibers and Hif-1α expression, compared with Modic II and ODI ≤ 40% groups, respectively. There were no differences in terms of Egr-1 expression.The discs with Modic I MRI signal could represent potential targets for medical treatments, whereas Modic II seems to be a more likely point of no return in a degenerative process. Therefore, further investigations are to better investigate inflammatory pathways and degenerative mechanisms in DDD.

Lipopolysaccharide (LPS)-induced inflammation causes massive threatening diseases, such as sepsis, acute lung injury and multiple organ dysfunction syndrome. Efficient treatment to prevent inflammation is crucial in LPS-induced inflammatory diseases. Heat-clearing Chinese medicines (CMs) have been used to ameliorate LPS-induced inflammation in China for centuries. Heat-clearing CMs regulate inflammatory pathways, thereby inhibiting the release of inflammatory factors. This review aimed to introduce promising heat-clearing CMs countering LPS-induced inflammation in the last 5 years, exploring the underlying molecular mechanisms.

Despite enduring diverse insults, mitochondria maintain normal functions through mitochondrial quality control. However, the failure of mitochondrial quality control resulting from excess damage and mechanical defects causes mitochondrial dysfunction, leading to various human diseases. Recent studies have reported that mitochondrial defects are found in Alzheimer's disease (AD) and worsen AD symptoms. In AD pathogenesis, mitochondrial dysfunction-driven generation of reactive oxygen species (ROS) and their contribution to neuronal damage has been widely studied. In contrast, studies on mitochondrial dysfunction-associated inflammatory responses have been relatively scarce. Moreover, ROS produced upon failure of mitochondrial quality control may be linked to the inflammatory response and influence the progression of AD. Thus, this review will focus on inflammatory pathways that are associated with and initiated through defective mitochondria and will summarize recent progress on the role of mitochondria-mediated inflammation in AD. We will also discuss how reducing mitochondrial dysfunction-mediated inflammation could affect AD. [BMB Reports 2020; 53(1): 35-46].

Cardiovascular disease (CVD) is the leading cause of death globally. People living with type 2 diabetes mellitus (T2DM) have up to three times higher risk of developing CVD, particularly heart failure with preserved ejection fraction (HFpEF), for which there is no effective treatment. The need for tangible interventions has led to investigations into a number of biomarkers associated with metabolic and vascular dysfunction that could be utilised for diagnostic and treatment purposes. This review discusses the importance and mechanisms of inflammatory and angiogenic biomarkers, which have shown the most potential in the pathogenesis and diagnosis of HFpEF, particularly in the presence of diabetes. In depth “in silico” analysis was also carried out to identify pathogenic pathways associated with HFpEF, both in the presence and absence of diabetes. The results identified mostly inflammatory pathways associated with HFpEF in the presence of diabetes, and a number of pathways related to angiogenesis, remodelling, metabolism as well as inflammation, in the absence of diabetes. The shared and unique pathways identified in HFpEF in the presence and absence of diabetes, should be explored further in order to improve management and outcomes of people living with HFpEF, taking into the account other underlying conditions.

A predominant source of complication in SARS-CoV-2 patients arises from thecytokine storm, an elevated expression of inflammatory helper T-cell associated cytokines that can lead to tissue damage and organ failure. The high inflammatory burden of this viral infection often results in cardiovascular comorbidities. A better understanding of the interaction between thecytokine stormand cardiovascular proteins might inform medical decisions and therapeutic approaches. We hypothesized that all major helper T-cell inflammatory pathways (Th1, Th2 and Th17) synergistically contribute to cardiometabolic modifications in serum of COVID-19 patients. We proved our hypothesis by integrating Th1, Th2 and Th17 cytokines to predict expression of cardiometabolic proteins profiled by OLINK proteomics.

The prevalence, incidence and mortality rates of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are gradually increasing. New approaches are being developed to manage the progression and treatment of neurodegenerative diseases. Catechins, polyphenolic compounds, are key compounds that demonstrate therapeutic effects with their properties such as antioxidant, anti-inflammatory, anti-apoptotic properties in the prevention and treatment of neurodegenerative diseases. The therapeutic effects of catechins have been exhaustively studied in human and animal models. Catechins can have anti-inflammatory effects by suppressing inflammatory pathways and cytokines, as well as antioxidant effects such as chelating metal ions and scavenging radicals. They might reduce phosphorylation of tau proteins, aggregation of amyloid-beta and apoptotic proteins release. They can also decrease alpha-synuclein accumulation and increase dopamine levels. With all these effects, they can have an effect on neurodegenerative diseases. This review points to the potential mechanisms of catechins in neurodegenerative diseases, based on their findings in the literature review. Key teaching pointsCatechins can reduce amyloid-β plaque aggregation and tau phosphorylation.Catechins can decrease alfa-synuclein levels.Catechins can protect neuronal cells with their anti-apoptotic effect.More comprehensive studies are needed to clarify this issue.

Summary: Accumulating evidence supports the impact of the gut microbiota on the clinical efficacy of cancer immunotherapies against extraintestinal tumors, but it has not yet been addressed whether local commensals could also dictate the prognosis of patients with cancer. In this issue of Cancer Discovery, Tsay and colleagues demonstrate that the lower airway microbiota may harbor oral commensals that turn on IL17-mediated inflammatory pathways and reprogram host transcription to exacerbate lung cancer progression. See related article by Tsay et al., p. 293.

BackgroundNeurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, however current management focuses on symptom mitigation, with no approved treatments targeting disease mechanisms. There is accumulating literature implicating the immune system in NDDs, and transcriptomics of post-mortem brain tissue from individuals with NDDs has revealed an inflammatory signal. MethodsWe interrogated two RNA-sequencing datasets of ASD and TS (compared to age-matched controls) and identified the top 1000 differentially expressed genes, to explore commonly enriched pathways using an over-representation analysis through GO, KEGG and Reactome.ResultsIn the ASD analysis, the top 1000 DEGs enriched 754 GO terms (all upregulated), 55 KEGG pathways (54 upregulated), and 109 Reactome pathways (all upregulated), involving inflammation, cytokines, complement, cell signalling and epigenetic regulation. In the TS analysis, the top 1000 DEGs enriched 419 GO terms (416 upregulated), 56 KEGG pathways (all upregulated), and 28 Reactome (all upregulated) pathways, including inflammation, cytokines, signal transduction and immune response to stimuli. Of the top 1000 DEGs from the ASD and TS analyses, 133 DEGs were shared. Interaction networks of the common protein-coding DEGs using STRING revealed 5 central up-regulated hub genes: CSF2RB, HCK, HCLS1, LCP2 and PLEK, which are all kinases involved in cell signalling. Applying KEGG and Reactome analysis to these common DEGs identified pathways involving interleukins, complement activation, and cell signalling pathways. ConclusionsThese findings bring new evidence of shared inflammation in ASD and TS, and provide therapeutic opportunities targeting inflammation, epigenetic machinery, and cell signalling including kinases.

BACKGROUND AND AIM: Global prevalence of type 2 diabetes (T2DM) is increasing. Research has identified links between air pollution exposure and T2DM through metabolic and inflammatory pathways, but...

Actinic prurigo is a rare, idiopathic chronic photodermatosis of childhood characterized by excoriated papules, nodules, and plaques in sun-exposed areas. It is notoriously difficult to treat. The disorder involves a type IV hypersensitivity reaction driven by both Th1 and Th2 inflammatory pathways, the latter of which leads to secretion of IL-4, IL-5, IL-13, and production of B cells, IgE, and IgG4. Dupilumab, an IL-4 receptor antagonist, disrupts the Th2 pathway. We present a pediatric patient with severe, recalcitrant actinic prurigo who achieved rapid and sustained clearance with dupilumab.

Deleterious consequences like acute kidney injury frequently occur upon successful resuscitation from cardiac arrest. Extracorporeal life support is increasingly used to overcome high cardiac arrest mortality. Carbon monoxide (CO) is an endogenous gasotransmitter, capable of reducing renal injury. In our study, we hypothesized that addition of CO to extracorporeal resuscitation hampers severity of renal injury in a porcine model of cardiac arrest. Hypoxic cardiac arrest was induced in pigs. Animals were resuscitated using a conventional [cardiopulmonary resuscitation (CPR)], an extracorporeal (E-CPR), or a CO-assisted extracorporeal (CO-E-CPR) protocol. CO was applied using a membrane-controlled releasing system. Markers of renal injury were measured, and histopathological analyses were carried out. We investigated renal pathways involving inflammation as well as apoptotic cell death. No differences in serum neutrophil gelatinase-associated lipocalin (NGAL) were detected after CO treatment compared with Sham animals (Sham 71 ± 7 and CO-E-CPR 95 ± 6 ng/mL), while NGAL was increased in CPR and E-CPR groups (CPR 135 ± 11 and E-CPR 124 ± 5 ng/mL; P < 0.05). Evidence for histopathological damage was abrogated after CO application. CO increased renal heat shock protein 70 expression and reduced inducible cyclooxygenase 2 (CPR: 60 ± 8; E-CPR 56 ± 8; CO-E-CPR 31 ± 3 µg/mL; P < 0.05). Caspase 3 activity was decreased (CPR 1,469 ± 276; E-CPR 1,670 ± 225; CO-E-CPR 755 ± 83 pg/mL; P < 0.05). Furthermore, we found a reduction in renal inflammatory signaling upon CO treatment. Our data demonstrate improved renal function by extracorporeal CO treatment in a porcine model of cardiac arrest. CO reduced proinflammatory and proapoptotic signaling, characterizing beneficial aspects of a novel treatment option to overcome high mortality.

Cerebral aneurysms (CAs) are characterized by a pathological wall structure with internal elastic lamina and media disruption, which leads to focal weakened pouches of the arterial wall. The prevalence of unruptured CAs has been estimated to be 2%-5% in the general population. During the past few decades, the pathophysiological mechanisms behind the formation, growth, and rupture of CAs have been the focus of numerous research studies. In the present review, we have summarized the inflammatory pathways, genetics, and risk factors for the formation, growth, and rupture of CAs. In addition, we have discussed the concepts of geometric indexes, flow patterns, and fluid dynamics that govern CA development.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer characterized by the presence of many dermal tumor emboli in the papillary and reticular dermis of the skin overlying the breast. IBC patients, compared to other breast cancer patients, have more frequently metastatic axillary lymph nodes. IBC is often high grade, negative for hormone receptors and presents with amplification of the HER2 gene. Invasive IBC is frequently of ductal phenotype, even if a specific histological distinction for these lesions has not been described. The pathogenesis and evolution of IBC are strongly dependent upon tumor microenvironment, characterized by several macrophages/monocytes and lymphocytes. The tumor and microenvironment cells are well molecularly characterized, showing the main contributor of inflammatory pathways in tumor biology of IBC. In addition, several molecular alterations are described in this tumor, such as mutations of ERBB2, KRAS, BRAF, EGFR, PIK3CA, PTEN, AKT1 , and AKT3 genes that could suggest a therapeutic stratification of IBC patients with the combination of different biological target therapies.

Monoclonal antibodies block specific inflammatory pathways involved in the pathogenesis of asthma. These pathways are important in host defense against pathogens, and in particular, against parasites. Despite theoretical concerns about infection risk, biologics seem to have a favorable safety profile. Data from large clinical trials and postmarketing surveillance for these drugs have not shown increases in severe infections, including those from parasitic organisms. This may be due to redundancy of effector cells within the immune system. Certain drugs have special considerations and precautions, and therefore, the prescribing physician should be familiar with product recommendations and warnings.

Anemia is a common, yet often overlooked, geriatric syndrome characterized by reduced hemoglobin levels and associated with adverse health outcomes and early mortality. Evidence suggests that anemia is an independent risk factor for frailty in older adults. In this article, the authors review the evidence for the role of chronic inflammation in the pathogenesis of anemia in the frail elderly. Understanding the relationships between anemia, frailty, and chronic inflammation will pave the way for the development of novel interventional strategies for the treatment and prevention of anemia and, likely, also frailty in older adults.

Glioma is the oneof the most prevalent primarybrain tumors. There is a variety of oxidative stresses, inflammatory pathways, apoptosis signaling, and Na+ /H + exchangers (NHEs) involved in the pathophysiology of glioma. Previous studies have indicated a relationship between NHEs and some molecular pathways in glioma. NHEs, including NHE1, NHE5, and NHE9 affect apoptosis, tumor-associated macrophage inflammatory pathways, matrix metalloproteinases, cancer-cell growth, invasion, and migration of glioma. Also, inhibition of NHEs contributes to increased survival in animal models of glioma. Limited studies, however, have assessed the relationship between NHEs and molecular pathways in glioma. This review summarizes current knowledge and evidence regarding the relationship between NHEs and glioma, and the mechanisms involved.

While tobacco cigarette (TC) smoking has continued to drop to all-time lows, the use of electronic cigarettes (ECs), introduced in the US in 2007, has been rising dramatically, especially among youth. In EC emissions, nicotine is the major biologically active element, while levels of carcinogens and harmful combustion products that typify TC smoke are very low or even undetectable. TCs cause cardiovascular harm by activation of inflammatory pathways and oxidative damage, leading to atherogenesis and thrombosis, as well as through sympathetic activation triggering ischemia and arrhythmia. While ECs are generally believed to be safer than TCs, there remain many uncertainties regarding the overall cardiovascular health effects of EC usage. In this review, we discuss the various components of EC smoke and review the potential mechanisms of cardiovascular injury caused by EC use. We also discuss the controversy regarding the increasing epidemic of youth EC use weighed against the use of ECs as a smoking-cessation aid.

Response to biologic therapies in severe asthma is variable, with patients being either nonresponders, responders or super-responders. There is currently no explanation for this variation in response. If asthma-specific inflammatory pathways are part of a wider network of pathogenic mechanisms (including systemic inflammation), then the state of this wider network could either help or hinder the effect of the biologic. People with severe asthma are often polysymptomatic with a variable frequency of nonrespiratory symptoms. Application of existing network theory would predict that high systemic inflammation, measurable by the frequency of nonrespiratory symptoms, should decrease the effectiveness of biologics, a prediction consistent with the limited existing data. A detailed examination of the relationship between biologic response and the frequency or profile of nonrespiratory symptoms would provide a testable prediction of this hypothesis. The clinical presentation of super-responders is consistent with biologics sometimes having a positive effect on the pathology (level of dysregulation) in a network system. If that were the case, then network theory predicts the possibility of a short-term increase in nonrespiratory symptoms prior to the improvement reported by super-responders. If biologics lead to less network dysregulation in some patients, then this raises the possibility of new applications for this therapy and of an improved response to biologics if lifestyle improvement is started prior to biologic therapy.

To study thrombin (TM) damage effect and detailed quantitative relation on cerebral vessels function, and to explore inflammatory mechanism of TM on cerebral vasospasm (CVS) in vivo. Wild type SD rats were randomly assigned into different groups for further experiments. Subarachnoid hemorrhage (SAH) rat model was established with double injections of the autogenous blood into the cisterna magna. TM injection was performed during the first injection of the autogenous blood. Primary groups were control group, SAH group TM group and TM+SAH group. In addition, TM+SAH group contains several groups with different injection doses or TM intervention duration. HE staining was performed to detect injury of cerebral basilar artery. Histopathologic examination was performed to detect intra-lumen area of cerebral basilar artery. Each specimen was to be detected the expressive level of Proteinase-activated Receptor-1 (PAR-1) and Tumor necrosis factor-α (TNF-α) by immunohistochemistry. The mean optical density (MOD) values of PAR-1 and TNF-α were used as the semiquantitative indicators to conduct statistical analysis. Compared with the control group, the rat basilar artery intra-lumen area of TM group and TM+SAH group were significantly smaller (P < 0.05), while MOD value of PAR-1 and TNF-α of basilar artery were higher (P < 0.05). With equal dose of TM, the basilar artery intra-lumen area of TM+SAH group are larger than SAH group (P < 0.05), suggesting TM exacerbated SAH injury. Among TM+SAM sub-groups, with the TM concentration increased, the basilar artery intra-lumen area became smaller, and the MOD value of PAR-1 and TNF-α of basilar artery gradually increased, suggesting CVS effect of TM was dose-dependent. Meanwhile, CVS effect of TM was also time-dependent, verified by comparisons of sub-groups with different TM intervention duration (P < 0.05). Thrombin induces CVS effect to aggravate SAH injury via PAR-1/TNF-α inflammatory pathways. Such pathological role of TM was both dose-dependent and time-dependent.

The current state, tools, and applications of personalized medicine with special emphasis on inflammatory skin diseases like psoriasis and atopic dermatitis are discussed. Inflammatory pathways are outlined as well as potential targets for monoclonal antibodies and small‐molecule inhibitors.

Non-alcoholic steatohepatitis (NASH), also known as fatty liver disease (FLD), is a major public health problem. It is considered to be the hepatic manifestation of the metabolic syndrome. Chronic inflammation of the liver is an essential key in the progression from simple hepatic steatosis to steatohepatitis, the evolutionary stage of fatty liver disease. Moreover, the innate immune system plays a crucial role in the progression of hepatic inflammation. For this reason, it is of utmost importance to elucidate the connections between immune mechanisms, Toll-like receptor cytokine signalling, in order to find new effective treatments. Further studies are necessary to test theories presented in this paper. The elucidation of mechanisms underlying the progression of hepatic steatosis towards steatohepatitis is essential for the development of useful diagnosis and treatment for medical practice.

During the last few years, a significant number of studies have attempted to clarify the underlying mechanisms that lead to the presentation of atrial fibrillation (AF). Inflammation is a key component of the pathophysiological processes that lead to the development of AF; the amplification of inflammatory pathways triggers AF, and, in tandem, AF increases the inflammatory state. Indeed, the plasma levels of several inflammatory biomarkers are elevated in patients with AF. In addition, the levels of specific inflammatory biomarkers may provide information regarding to the AF duration. Several small studies have assessed the role of anti-inflammatory treatment in atrial fibrillation but the results have been contradictory. Large-scale studies are needed to evaluate the role of inflammation in AF and whether anti-inflammatory medications should be routinely administered to patients with AF.

The cyclic dinucleotide-cGAS–STING axis plays important roles in host immunity. Activation of this signaling pathway, via cytosolic sensing of bacterial-derived c-di-GMP/c-di-AMP or host-derived cGAMP, leads to the production of inflammatory interferons and cytokines that help resolve infection. Small molecule activators of the cGAS–STING axis have the potential to augment immune response against various pathogens or cancer. The aberrant activation of this pathway, due to gain-of-function mutations in any of the proteins that are part of the signaling axis, could lead to various autoimmune diseases. Inhibiting various nodes of the cGAS–STING axis could provide relief to patients with autoimmune diseases. Many excellent reviews on the cGAS–STING axis have been published recently, and these have mainly focused on the molecular details of the cGAS–STING pathway. This review however focuses on small molecules that can be used to modulate various aspects of the cGAS–STING pathway, as well as other parallel inflammatory pathways.

Background: Coronavirus disease 2019 (COVID-19) is now a worldwide public health crisis. The causative pathogen is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Novel therapeutic agents are desperately needed. Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARS-CoV-2 may produce a broader range of therapies. Glycyrrhizic acid (GA) might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. However, the mechanism underlying how GA regulates host factors remains to be determined.Methods: In our report, we conducted a bioinformatics analysis to identify possible GA targets, biological functions, protein-protein interactions, transcription-factor-gene interactions, transcription-factor-miRNA coregulatory networks, and the signaling pathways of GA against COVID-19.Results: Protein-protein interactions and network analysis showed that ICAM1, MMP9, TLR2, and SOCS3 had higher degree values, which may be key targets of GA for COVID-19. GO analysis indicated that the response to reactive oxygen species was significantly enriched. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-α, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with common targets and the activity of TFs were also recognized.Conclusions: GA may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.

Accumulating evidence have positioned inflammatory signaling pathways as crucial routes by which microbes inhabiting the gastrointestinal tract (the gut microbiota) communicate with the host brain to influence behavior, with impacts on mental illnesses. In this short review, an overview of inflammatory and gut microbiota status in human depression and in rodent models of the illness are provided. Next, potential inflammatory pathways mediating the communications between the gut and the brain under stressful conditions are described. Finally, dietary interventions targeting the gut microbiota-immune-brain axis in the context of depression are briefly discussed.

Abstract: There is an increase in the incidence of inflammatory eye diseases worldwide. Several dysregulated inflammatory pathways, including the NOD-like receptor protein 3 (NLRP3) inflammasome, have been reported to contribute significantly to the pathogenesis and progression of ophthalmic diseases. Although the available allopathic/ conventional medicine has demonstrated effectiveness in managing eye diseases, there is an ongoing global demand for alternative therapeutics with minimal adverse drug reactions, easy availability, increase in patient compliance, and better disease outcomes. Therefore, several studies are investigating the utilization of natural products and herbal formulations in impeding inflammatory pathways, including the NLRP3 inflammasome, in order to prevent or manage eye diseases. In the present review, we highlight the recently reported inflammatory pathways with special emphasis on NLRP3 Inflammasomes involved in the development of eye diseases. Furthermore, we present a variety of natural products and phytochemicals that were reported to interfere with these pathways and their underlying mechanisms of action. These natural products represent potential therapeutic applications for the treatment of several inflammatory eye diseases.

Generalized pustular psoriasis (GPP) is a rare and severe auto-inflammatory skin disease that is characterized by recurrent, acute onset, and generalized pustular eruptions on erythematous, inflamed skin. GPP is traditionally classified as a variant of psoriasis vulgaris, even though recent clinical, histological and genetic evidence suggests that it is a heterogeneous disease and requires a separate diagnosis. In recent years, variants of IL36RN, CARD14, AP1S3 and MPO genes have been identified as causative or contributing to genetic defects in a proportion of patients affected by GPP. These disease-related genes are involved in common inflammatory pathways, in particular in the IL-1/IL-36-chemokines-neutrophil pathogenic axis. At present, no standard therapeutic guidelines have been established for GPP management, and there is a profound need for novel efficacious treatments of GPP. Among them, biological agents antagonizing the IL-36 pathway are promising therapeutics. The aim of the present review is to provide the most recent updates on the genetics, genotype-phenotype correlation and pathological basis of GPP, as well as on biologic treatments available for GPP and relative clinical courses.

Atherosclerosis, a dominant and growing cause of death and disability worldwide, involves inflammation from its inception to the emergence of complications. Targeting inflammatory pathways could therefore provide a promising new avenue to prevent and treat atherosclerosis. Indeed, clinical studies have now demonstrated unequivocally that modulation of inflammation can forestall the clinical complications of atherosclerosis. This progress pinpoints the need for preclinical investigations to refine strategies for combatting inflammation in the human disease. In this Review, we consider a gamut of attractive possibilities for modifying inflammation in atherosclerosis, including targeting pivotal inflammatory pathways such as the inflammasomes, inhibiting cytokines, manipulating adaptive immunity and promoting pro-resolution mechanisms. Along with lifestyle measures, pharmacological interventions to mute inflammation could complement traditional targets, such as lipids and hypertension, to make new inroads into the management of atherosclerotic risk., The contribution of inflammation to atherosclerosis is substantial, and is just beginning to be understood. In this Review, Soehnlein and Libby discuss how inflammation promotes atherosclerosis and its consequences, and how such processes could be targeted therapeutically. The potential pitfalls of targeting immune processes — namely the increased potential for infections — are also discussed, along with ways to modulate cardiovascular therapies in time and space to make them more effective.

Skin is the largest and most complex organ in the human body comprised of multiple layers with different types of cells. Different kinds of environmental stressors, for example, ultraviolet radiation (UVR), temperature, air pollutants, smoking, and diet, accelerate skin aging by stimulating inflammatory molecules. Skin aging caused by UVR is characterized by loss of elasticity, fine lines, wrinkles, reduced epidermal and dermal components, increased epidermal permeability, delayed wound healing, and approximately 90% of skin aging. These external factors can cause aging through reactive oxygen species (ROS)-mediated inflammation, as well as aged skin is a source of circulatory inflammatory molecules which accelerate skin aging and cause aging-related diseases. This review article focuses on the inflammatory pathways associated with UVR-mediated skin aging.

Background: Fruits are an important dietary component, which supply vitamins, minerals, as well as dietary fiber. In addition, they are rich sources of various biological and pharmacologically active compounds. Among these, temperate fruits are well studied for their pharmacological potentials, whereas tropical/subtropical fruits are less explored for their health impacts. In India, most of the consumed fruits are either tropical or subtropical. Objectives: The present review aims to provide a health impact of major tropical and sub-tropical fruits of India, emphasizing their anticancer efficacy. In addition, the identified bioactive components from these fruits exhibiting anticancer efficacy are also discussed along with the patent literature published. Methods: The literature was collected from various repositories, including NCBI, ScienceDirect, Eurekaselect, and Web of Science; literature from predatory journals was omitted during the process. Patent literature was collected from google patents and similar patent databases. Results: Tropical fruits are rich sources of various nutrients and bioactive components including polyphenols, flavonoids, anthocyanin, etc. By virtue of these biomolecules, tropical fruits have been shown to interfere with various steps in carcinogenesis, metastasis, and drug resistance. Their mode of action is either by activation of apoptosis, regulation of cell cycle, inhibition of cell survival and proliferation pathways, increased lipid trafficking or inhibiting inflammatory pathways. Several molecules and combinations have been patented for their anticancer and chemoprotective properties. Conclusion: Overall, the present concludes that Indian tropical/ subtropical fruits are nutritionally and pharmacologically active and may serve as a source of novel anticancer agents in the future.

Many genetic factors are involved in the pathogenesis of rheumatoid arthritis (RA). This study is aimed to summarize the literature regarding the relationship between variation in the genes encoding NLRP3/CARD8 and RA, using a candidate polymorphism approach. Several investigations have been conducted on the association of the genetic alterations of the NLRP3 p.Q705K and CARD8 p.C10X with the inflammatory diseases. Although there are variable results, the role of inflammatory pathways and genes involved is undeniable. The genetic context of the NLRP3 p.Q705K and CARD8 p.C10X gene variants in the pathogenesis of RA is still unclear to confirm that these variations show a pivotal role in the pathophysiology of RA. More comprehensive studies in this area seem to be needed.

Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.